Coenzyme Q is an essential component widely distributed in living organisms from bacteria to mammals, and is known as a component of mitochondrial electron transfer system in cells in the living body. Coenzyme Q serves as a transfer component in the electron transfer system by the repetition of oxidation and reduction in mitochondria, and, further, reduced coenzyme Q is known to have antioxidant activity. The major component in humans is coenzyme Q10 which is one having 10 isoprenoid repeating structures in its side chain, and, usually, about 40 to 90% thereof is present in the living body as the reduced form. The physiological activity of coenzyme Q includes activation of energy production by mitochondrial activation, activation of cardiac function, an effect of stabilizing cell membranes, and an effect of protecting cells by antioxidant activity.
While coenzyme Q10 currently produced and sold is, in large part, oxidized coenzyme Q10, reduced coenzyme Q10 which exhibits higher oral absorbability than that of oxidized coenzyme Q10 has also been commercially available and has come to be used in recent years.
Patent Literature 1 discloses a common method for obtaining reduced coenzyme Q10. Furthermore, several methods for obtaining reduced coenzyme Q10 as a crystal are also known. For example, in Patent Literature 2, reduced coenzyme Q10 is produced as a crystal by crystallization in an alcohol solution and/or a ketone solution. In Patent Literature 3, reduced coenzyme Q10 is crystallized by adding the high concentration liquid phase thereof to a poor solvent.
In addition, Patent Literature 4 discloses that reduced coenzyme Q10 is dissolved in oil and fat and then cooled, thereby making it possible to yield a crystal which has a different X-ray diffraction pattern from that of a usual reduced coenzyme Q10 crystal and is excellent in stability.
Reduced coenzyme Q10 is known to usually have a property such that it is easily oxidized in the presence of molecular oxygen to be converted into oxidized coenzyme Q10. In response, for example, Patent Literature 5 discloses, as a method for stabilizing reduced coenzyme Q10, a method for allowing reduced coenzyme Q10 to contact and coexist with ascorbic acids or citric acids. In addition, the conventional reduced coenzyme Q10 crystal has the property of being very easily electrostatically charged.
By the way, it has been reported for many compounds, whether organic compounds or inorganic compounds, that a plurality of crystal forms having different crystal structures are generally present, which are called “crystal polymorphs”. A plurality of crystal forms in a crystal polymorphism each show different patterns in analysis such as X-ray diffraction or infrared spectroscopic analysis, as well as have different physical properties such as melting point and solubility. In general, there is a tendency that a more energetically stable crystal form under the defined conditions has a higher melting point and a lower solubility, and a crystal form having the highest melting point and the lowest solubility is usually called “stable form”. In the case of a crystal form other than the stable form, transition to the stable form can occur during operation such as crystallization, drying, or pulverization. The transition is a very natural phenomenon that a substance changes toward an energetically stable state, but physical properties of the resulting crystal also change due to such a phenomenon, thereby possibly causing the crystal or a formulation containing such a crystal as an active ingredient to have problems in terms of quality. The crystal in the stable form not only causes no such transition but also has a high melting point as described above, thereby making it possible to be dried at a higher temperature during drying thereof, and has a low solubility, thereby making it possible to yield a crystal in a larger amount during crystallization, and, therefore, has an advantage of increasing efficiency at the time of production. For such reasons, in the case where a compound whose crystal polymorphs are present is utilized for, in particular, medical applications or the like, it is important to select an optimal crystal form such as the stable form.
It has also been reported that different crystal forms have different electrostatic charges. If a crystal takes an electrostatic charge, its sticking to equipment at the time of production, or the like, not only decreases the efficiency at the production but also causes problems in terms of safety, such as dust explosion and contamination of facilities/workers. In the case of a compound having crystal polymorphs, selecting the optimal crystal polymorph can be one effective measure against the above problems. For example, in Patent Literature 6, it has been reported that a new crystal form (type IV) of a 1,2-dihydropyridine compound has a lower electrostatic charge than other crystal forms.